Communication between cells is often mediated by secreted signaling molecules that bind cell surface receptors and modulate the activity of specific intracellular effectors. The Wnt family of secreted glycoproteins is one group of signaling molecules that has been shown to control a variety of developmental processes, including cell fate specification, cell proliferation, cell polarity and cell migration. In addition, mis-regulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. The Wnt growth factor family includes more than 10 genes identified in the mouse and at least 7 genes identified in the human.
Studies of mutations in Wnt genes have indicated a role for Wnts in growth control and tissue patterning. The Wnt-1 proto-oncogene (int-1) was originally identified from mammary tumors induced by mouse mammary tumor virus (MMTV) due to an insertion of viral DNA sequence. Knock-out mutations in mice have shown Wnts to be essential for brain development, and the outgrowth of embryonic primordia for kidney, tail bud, and limb bud. Overexpression of Wnts in the mammary gland can result in mammary hyperplasia, and precocious alveolar development.
In Drosophila, Wingless signaling mediates endoderm induction and the establishment of segment polarity in the developing embryo. The fly Wingless cascade is strikingly similar to the vertebrate Wnt signaling pathway, which controls a number of key developmental decisions such as dorsal-ventral patterning in Xenopus.
The molecular mechanisms by which the Wnt signal regulates cellular functions are becoming increasingly well understood. Wnt stabilizes cytoplasmic beta-catenin, which stimulates the expression of genes including c-myc, c-jun, fra-1, and cyclin D1. Axin, newly recognized as a component of the Wnt signalling pathway, negatively regulates this pathway. Other components of the Wnt signalling pathway, including Dvl, glycogen synthase kinase-3beta, beta-catenin, and adenomatous polyposis coli, interact with Axin, and the phosphorylation and stability of beta-catenin are regulated in the Axin complex.
Recent findings suggest that Wnt signals can sometimes play a permissive role during cell-fate assignment. Wnt proteins have been shown to interact with a number of extracellular and cell-surface proteins, whereas many intracellular components of the Wnt-signalling pathway are also involved in other cellular functions. These observations suggest that the future understanding of Wnt signalling may require models that are based on a signalling network rather than a single linear pathway. Identification of the members of this network are of particular interest for their role in cellular differentation and growth.
Relevant Literature
The role of negative feedback mechanisms and their roles during pattern formation are discussed by Perrmon et al. (1999) Cell 97, 13-16.
The role of Wnt signaling in animal development is discussed by Cadigan and Nusse (1997) Genes Dev 11, 3286-3305. The effect of engrailed and hedgehog on wingless are discussed in Sanson et al. (1999) Cell 98, 207-216.
The patterning of the Drosophila embryonic epidermis, and the role onf wingless in epidermis patterning is discussed by DiNardo et al. (1994) Curr Opin Genet Dev 4, 529-534; and Bejsovec and Martinez (1991) Development 113, 471-485. Pazdera et al. (1998) Development 125, 3427-3436 disclose patterned epidermal cell death in wild-type and segment polarity mutant Drosophila embryos. Moline et al. (1999) Development 126, 4375-4384 show that directionality of Wingless protein transport influences epidermal patterning in the Drosophila embryo.
Isolated nucleotide compositions and sequences are provided for naked cuticle (nkd) genes. The nkd nucleic acid compositions find use in identifying homologous or related genes; in producing compositions that modulate the expression or function of its encoded protein, Nkd; for gene therapy; mapping functional regions of the protein; and in studying associated physiological pathways. In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as treatment of cancer, identification of cell type based on expression, and the like.
The segment-polarity gene, naked cuticle (nkd), is shown to limit the effects of Wnt signaling. nkd expression can be inducible by Wnt signaling. nkd encodes a novel protein with a single EF-hand most similar to the recoverin family of myristoyl switch proteins and may link ion fluxes to the regulation of Wnt signal potency, duration, or distribution. Nkd proteins may restrain responses to Wnt proteins in their many roles in vertebrate development and disease.